Silent agonists for α7 nicotinic acetylcholine receptors.
1-ethyl-4-phenylthiomorpholin-1-ium (PubChem CID: 137630553)
Allosteric modulation
Desensitization
GTS-21 (3-(2,4-dimethoxy-benzylidene)anabaseine) (PubChem CID: 5310985)
Inflammation
NS6740 (1,4-Diazabicyclo[3.2.2]non-4-yl[5-[3-(trifluoromethyl)phenyl]− 2-furanyl]methanone) (PubChem CID: 10021664)
Nicotinic acetylcholine receptor
PNU-120596 (1-(5-chloro-2,4-dimethoxyphenyl)− 3-(5-methylisoxazol-3-yl)urea) (PubChem CID: 311434)
Signal transduction
Journal
Pharmacological research
ISSN: 1096-1186
Titre abrégé: Pharmacol Res
Pays: Netherlands
ID NLM: 8907422
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
received:
10
12
2022
revised:
07
03
2023
accepted:
14
03
2023
medline:
10
4
2023
pubmed:
21
3
2023
entrez:
20
3
2023
Statut:
ppublish
Résumé
We discuss models for the activation and desensitization of α7 nicotinic acetylcholine receptors (nAChRs) and the effects of efficacious type II positive allosteric modulators (PAMs) that destabilize α7 desensitized states. Type II PAMs such as PNU-120596 can be used to distinguish inactive compounds from silent agonists, compounds that produce little or no channel activation but stabilize the non-conducting conformations associated with desensitization. We discuss the effects of α7 nAChRs in cells of the immune system and their roles in modulating inflammation and pain through what has come to be known as the cholinergic anti-inflammatory system (CAS). Cells controlling CAS do not generate ion channel currents but rather respond to α7 drugs by modulating intracellular signaling pathways analogous to the effects of metabotropic receptors. Metabotropic signaling by α7 receptors appears to be mediated by receptors in nonconducting conformations and can be accomplished by silent agonists. We discuss electrophysiological structure-activity relationships for α7 silent agonists and their use in cell-based and in vivo assays for CAS regulation. We discuss the strongly desensitizing partial agonist GTS-21 and its effectiveness in modulation of CAS. We also review the properties of the silent agonist NS6740, which is remarkably effective at maintaining α7 receptors in PAM-sensitive desensitized states. Most silent agonists bind to sites overlapping those for orthosteric agonists, but some appear to bind to allosteric sites. Finally, we discuss α9* nAChRs and their potential role in CAS, and ligands that will be useful in defining and distinguishing the specific roles of α7 and α9 in CAS.
Identifiants
pubmed: 36940890
pii: S1043-6618(23)00092-0
doi: 10.1016/j.phrs.2023.106736
pii:
doi:
Substances chimiques
alpha7 Nicotinic Acetylcholine Receptor
0
Receptors, Nicotinic
0
Anti-Inflammatory Agents
0
Types de publication
Journal Article
Review
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
106736Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest Two of the authors (RLP, and MQ) are inventors on a patent held by the University of Florida. Silent Agonists for the alpha7 nicotinic acetylcholine receptor: United States Letters Patent No. 11,155,551 for "NICOTINIC ACETYLCHOLINE RECEPTOR SILENT AGONISTS." issued on October 26, 2021.